[unreadable] One of the primary byproducts of acute allergic (IgE-mediated type I hypersensitivity) reactions is the generation of arachidonic acid from inflammatory cell membranes. Work by several investigators in in vitro systems suggests that arachidonic acid metabolites, particularly PGE2, may have immunomodulatory effects. However, conflicting results from these in vitro studies have not yielded solid conclusions on the actual roles of these mediators in the development of allergic inflammation. Using an in vivo murine model of type I hypersensitivity to ovalbumin, we have recently reported that inhibition of the cyclooxygenase pathway of arachidonic acid metabolism, and therefore PGE2 production, during the development of allergic inflammation conclusively caused a substantial increase in the allergic phenotype. More recently, we found that antibody neutralization of PGE2 in our model increased allergic inflammation. Additionally, in the same model, mice that lacked the PGE2 receptor EP1 also had significantly increased allergic inflammation. Based on our preliminary data, we hypothesize that PGE2 downregulates and inhibits lung-specific immune responses. The long-term goal of this proposal is to explore how PGE2 regulates inflammation and immune responses to allergens in the lung. In Specific Aim 1 we will define the immunomodulatory effects of PGE2 on the development of allergic disease. We will define the time (either antigen presentation or effector cell development) at which PGE2 has the greatest influence on Type 2 CD4+ T cell development using antibody neutralization of PGE2, exogenous administration of PGE2, and PGE2 synthase overexpressing mice. We will also determine if the immunomodulatory effect of PGE2 on allergic disease is through PGE2's regulation of leukotriene synthesis. In Specific Aim 2, we will determine the effect of signaling through the four different PGE2 receptors on the development of allergic inflammation in the lung. We will also determine the effect of signaling through the four EP receptors at the initial presentation of antigen on Type 2 cytokine production in vivo and test the effect of signaling through the EP receptors on the antigen-independent development of CD4+ T lymphocytes in vitro. Defining the role of PGE2 and the cellular receptors for PGE2 in the immunobiology of allergic inflammation in the lung may result in novel targets for drug development. [unreadable] [unreadable]